Project Summary Malignant gliomas are the most common cancer in adults. Mutations of isocitrate dehydrogenase 1 (IDH1) gene nearly invariably target Arg132, giving rise to the predominant IDH1R132H. Regarded as arguably the earliest and most common genetic event in glioma development, IDH1R132H is believed to be oncogenic, resulting from the gain of a neomorphic activity that produces the ?oncometabolite? 2-hydroxyglutarate. It is noteworthy, however, that heterozygous Idh1R132H in mice produced no glioma but rather reduced glioma penetrance. We have provided evidence that IDH1R132H is intrinsically suppressive of glioma initiation and growth. Whereas heterozygous IDH1R132H suppresses anchorage-independent growth, hemizygous IDH1R132H promotes neurosphere genesis, glioma stemness, and tumor growth. Conversely, anchorage-independent, but not -dependent, growth selects against particularly exogenous IDH1R132H expression. Furthermore, we have identified that IDH1R132H-heterozygous cells maintain a lower level of redox homeostasis than IDH1R132H- hemizygous cells. In this application, we hypothesize that heterozygous IDH1R132H negatively regulates redox homeostasis to suppress anchorage-independent growth, whereas loss of IDH1R132H heterozygosity undermines the regulation and promotes IDH1-wildtype-like phenotype. We propose to employ robust genomic approaches to the study of differential impact of IDH1R132H heterozygosity and hemizygosity on redox homeostasis and to explore the redox pathways as a therapeutic target of glioma progression.